Sigma-1 receptors are found throughout the central nervous system. Recent studies provide evidence for a role of sigma-1 receptors in schizophrenia. First, postmortem studies using the most selective radioligands have consistently revealed a decrease in sigma receptor density in the frontal cortex of schizophrenics compared to controls. Second, agonist binding at sigma-1 receptors facilitates N-methyl-D-aspartate (NMDA) stimulated dopamine release. In vivo, the release of dopamine evoked by sigma agonists occurs in the prefrontal cortex, a region where dopamine is intimately involved in the pathophysiology of negative and cognitive symptoms of the illness. Third, phase I clinical trials have indicated that atypical sigma-1 binding neuroleptics are effective in alleviating negative symptoms in some schizophrenics. Together, these data suggest that, in schizophrenia, alterations in sigma-1 receptor function might be associated with a deficit in glutamatergic and dopamine function in the prefrontal cortex. Yet, interpretation of postmortem changes in sigma-1 receptors has proven difficult, since most schizophrenics are on treatment prior to death. Therefore, Positron Emission Tomography (PET) measurement of sigma-1 receptors in drug-naive patients is critically needed to verify the decrease in sigma-1 receptor density in schizophrenia. PET methods are also essential to correlate sigma-1 receptor occupancy with the therapeutic or side effects of sigma-1 binding neuroleptics. The PI has designed a novel sigma-1 PET ligand, [18F]FPS, which has appropriate lipophilicity, stability, receptor affinity and selectivity to allow the accurate characterization sigma-1 receptors in vivo. Preliminary PET imaging experiments in non-human primates has confirmed the potential of this tracer to quantify sigma-1 receptors in the brain. An excellent correlation (R2=0.985) was observed between regional binding potential and reported sigma receptor densities in seven brain regions. The aim of this proposal is to fully develop [18F]FPS, including imaging and blocking experiments in baboons, toxicity studies and dosimetry estimates. In addition, the characterization of [18F]FPS binding in humans will be carried out. Upon successful completion of this work, clinical studies using this radiotracer will be proposed. The ability to measure sigma-1 receptors with PET is important, not only for schizophrenia, but also for other clinical indications, in which sigma receptor function is highly implicated, including disturbances in cognitive function and memory, and tumor imaging.